Usefulness of the BACES score in nontuberculous mycobacterial pulmonary disease for various clinical outcomes

A uniform prognostic marker is needed for nontuberculous mycobacterial pulmonary disease (NTM-PD) due to the diverse clinical course. We aimed to seek the utility of the BACES score, originally derived to predict all-cause mortality, for various outcomes. To calculate the BACES score, one point was given for each of the following factors: body mass index < 18.5 kg/m2, age ≥ 65 years, presence of cavities, elevated erythrocyte sedimentation rate, or male sex. The study included 681 patients, of whom 97 (14.2%), 189 (27.7%), 192 (28.2%), 143 (21.0%), 47 (6.9%), and 13 (1.9%) had BACES scores of 0 to 5. Those with greater BACES scores were more likely to experience dyspnea, body weight loss, and anorexia. With severe disease, the risk of disease progression increased while the rate of treatment culture conversion decreased. After adjustment of comorbidities, higher BACES score was independently associated with the risk of mortality from respiratory causes or infection. As a simple and efficient bedside tool for assessing the severity of NTM-PD, the BACES score has the potential to be utilized as a surrogate marker for uniform severity assessment.


Scientific Reports
| (2023) 13:7495 | https://doi.org/10.1038/s41598-023-33782-z www.nature.com/scientificreports/ who had previously received antibiotic therapy for NTM-PD, patients with insufficient data regarding the BACES score, or who were not followed up after diagnosis. Patient demographics, smoking history, symptoms, comorbidities, and chest computed tomography (CT) findings were retrieved from the electronic medical records. The date of NTM-PD diagnosis was defined as the date of the second culture-positive sputum collection or the date of culture-positive bronchoscopy specimen collection 18 . In contrast to the previous studies 13,19 , all NTM species, including Mycobacterium avium complex (MAC), Mycobacterium abscessus complex (MABC), and Mycobacterium kansasii, were included. When a different NTM species, not the one detected initially, was seen at least twice during follow-up, the infection was considered a mixed infection 18,20 .
The Institutional Review Board of Seoul National University Bundang Hospital (B-2203-743-102) approved this study and waived the requirement for informed consent due to the use of anonymized data and the study's retrospective nature. This study was conducted according to the principles of the Declaration of Helsinki.
Calculation of the BACES score. The BACES score is composed of five variables: BMI < 18.5 kg/m 2 , age ≥ 65 years, presence of a cavity on chest CT, elevated ESR (men > 15 mm/h, women > 20 mm/h), and male sex 13 . Chest CT findings and ESR within a year of diagnosis of NTM-PD but before treatment of the disease were used. Each variable was assigned one score, with a minimum score of 0 and a maximum score of 5. The estimated probabilities of 5-year mortality according to the BACES scores are reported as 1.2% for a score of 0, 3.2% for a score of 1, 8.4% for a score of 2, 21.3% for a score of 3, 47.8% for a score of 4, and 82.9% for a score of 5 13 . The patients were divided into three groups as follows: the mild (BACES score 0-1), moderate (BACES score 2-3), and severe (BACES score 4-5) groups 14 . Outcomes. Progression of NTM-PD was defined as the initiation of treatment for the disease [21][22][23] . Owing to the retrospective nature of the study, there was no uniform protocol for treating NTM-PDs, and attending physicians referred to the most recent American Thoracic Society/The Infectious Diseases Society of America/British Thoracic Society guidelines for appropriate treatment of the identified NTM species 2,3,17 . Culture conversion was defined as at least three consecutive negative sputum cultures after treatment. The day of collection of the first culture-negative sputum was considered the day of negative culture conversion 24 . The date and leading cause of death were collected from death certificates described by the attending physicians and confirmed using the Statistics Korea database using the Korean Standard Classification of Diseases, 7th edition, until December 31, 2020. Because there is no solid definition of NTM-PD-associated mortality 8 , two investigators (HJK and JHL) examined the causes of death associated with the respiratory system or infection were selected. Any discrepancies were resolved through group discussions. Details of the causes of death are listed in Supplementary Table S1.
Other statistical considerations. Categorical variables are expressed as numbers (percentiles) and p-values were calculated using the chi-square or Fisher's exact test. In contrast, continuous variables are expressed as median (interquartile range [IQR]), and p values were calculated using the Kruskal-Wallis test. For survival analyses, Kaplan-Meier curves were drawn, and p values were calculated using the log-rank test with Bonferroni adjustment for multiple comparisons. A Cox regression analysis was performed to calculate the hazard ratio (HR) with 95% confidence intervals (CIs). The p values of < 0.05 were considered statistically significant. Our observed data were utilized to calculate the 5-year probability of all-cause mortality using the Kaplan-Meier estimator.

Results
Baseline characteristics. Six hundred eighty-one patients were included in this study (Supplementary Patients with severe NTM-PD were more likely to have a smoking history (51.6%) than those with mild (11.2%) and moderate NTM-PD (34.1%) (p < 0.001 by chi-square test). A history of tuberculosis and chronic pulmonary comorbidities, such as chronic obstructive pulmonary disease, asthma, and idiopathic pulmonary fibrosis, were more common in patients with severe NTM-PD than in others. Compared to patients with moderate (71.6%) and mild (61.9%) NTM-PD, patients with severe NTM-PD were more likely to be diagnosed using two repetitive sputum cultures (83.3%) rather than invasive methods (p = 0.001 by chi-square test). Patients with severe NTM-PD also had a higher initial sputum smear positivity rate (36.7% vs. 10.5% vs. 6.6%, p < 0.001 by chi-square test) ( Table 1).

Discussion
This is the first study to validate the BACES score for various clinical aspects of NTM-PD in a separate cohort. With a higher BACES score, the prevalence of symptoms such as dyspnea, anorexia, and body weight loss was higher. The risk of disease progression increased with a higher BACES score, but the probability of negative culture conversion was lower after treatment. In addition to all-cause mortality, the BACES score was independently associated with mortality from respiratory causes or infections, even after adjusting for underlying comorbidities. The strengths of this study include the different patient groups, broader species of NTM, and a longer follow-up duration until death (median, 8.1 years) compared to those in a similar previous study (median, 6.8 years and 4.9 years for the derivation and validation groups, respectively) 13 .  Table 3. Factors associated with mortality due to respiratory cause or infection in NTM-PD patients. NTM-PD nontuberculous mycobacterial pulmonary disease; HR hazard ratio; COPD chronic obstructive pulmonary disease; IPF idiopathic pulmonary fibrosis. Numbers are presented as hazard ratios with 95% confidence intervals. *Statistically significant after multivariate adjustment (p < 0.05). www.nature.com/scientificreports/ Our results demonstrate that the BACES score is an integrated score comprising core prognostic components, which have been identified repeatedly in earlier studies. A lower BMI is associated with a higher prevalence of NTM-PD and a higher risk of all-cause and MAC-specific mortality 25,26 . Older age is a risk factor for all-cause mortality 19,[26][27][28][29][30] . The presence of cavities and elevated inflammatory markers are associated with a higher risk of radiographic deterioration, all-cause mortality, and MAC-specific mortality 26,28,29 . Men are more likely to die with NTM-PD than women 19,26,27 .
Initially, the BACES score was used to predict all-cause mortality in patients with NTM-PD 13 . In our study, the BACES score was also associated with a higher probability of disease progression, defined as the initiation of treatment. Although recent guidelines recommend initiating therapy for cavitary disease and positive smear results 3,12 , there is no definite standard to begin treatment, and shared decision-making is critical 15 . An objective measure of disease severity can be helpful in such circumstances, and the BACES score can be a valid parameter. In addition, the BACES score was associated with the probability of culture conversion after treatment, which was also observed in the original derivation cohort 14 .
We confirmed the association between the BACES score and mortality from respiratory causes or infection, even after adjustment for comorbidities. Patients are more likely to die "of " NTM-PD rather than "with" NTM-PD as the prevalence of NTM-PD increases 9 . However, given the high prevalence of comorbidities, it was challenging to identify the NTM-PD-specific deaths. As indicated in our study, patients with severe NTM-PD have a higher prevalence of underlying chronic lung diseases such as asthma, interstitial pulmonary fibrosis, and chronic obstructive pulmonary disease, which are essential factors influencing NTM-PD prognosis 26,27,29,30 . Although such chronic diseases affect survival, the BACES score is an independent predictor of mortality from respiratory causes or infection. This increases the scientific power of the BACES score as a prognostic marker in NTM-PD, regardless of the underlying medical conditions.
Negative culture conversion was associated with fewer deaths from respiratory causes or infections but not all-cause mortality. This differs from a previous study in which negative culture conversion observed within 6 to 12 months was associated with lower all-cause mortality 14 . Our study may be underpowered, considering that only 256 patients were included in the survival analysis of culture conversion, compared to approximately 700 patients in the original cohort 14 . Nonetheless, our results indicate that mortality from respiratory causes or infection can be reduced while eradicating NTM. We suggest that achieving culture conversion is essential regardless of the time to culture conversion. Taken together, patients with a higher BACES score had a higher risk of disease progression following treatment initiation, while the culture conversion rate was lower. Given the association between the achievement of culture conversion and better survival, those with a higher BACES score are less likely to survive.
This study has a few limitations. First, this study was conducted in South Korea, where the BACES score was developed. Further validation studies in other geographic areas and ethnicities are required. Second, due to the study's retrospective design, the treatment protocols could not be predefined. However, the overall rate of negative culture conversion was 54.4% in MAC-PD, 51.7% in MABC-PD, and 87.5% in Mycobacterium kansasii-PD, which is comparable with the findings from previous reports [31][32][33] . Thirdly, while the observed mortality rate was higher than that of the derivation cohort 13 , the proportion of patients with subjective symptoms was lower than that reported in a recent study 34 . This may be due to the older age of our patients compared to the original cohort (median 66 vs. 60 years) and because we did not use a detailed questionnaire-based symptom assessment, the attending physician may not have noticed mild or intermittent symptoms like cough, sputum, or dyspnea.

Conclusions
The BACES score is a simple integrated system associated with various clinical aspects. The BACES score might be a potential marker for disease progression, treatment response, death associated with the respiratory system or infection, and all-cause mortality. In addition to the recent recommendation of initiating treatment in patients with positive acid-bacilli smears and/or cavitary diseases 12 , those with a higher BACES score can receive aggressive treatment including intravenous antibiotics, rather than "watchful waiting. " Further studies are needed to determine whether aggressive therapy for patients with a higher BACES score is associated with better outcomes.

Data availability
The data supporting this study's findings are available from the corresponding author upon reasonable request. The data are not publicly available due to privacy or ethical restrictions.